Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A1, A2a, A2b, and A3, all of which modulate important physiological processes. For example, A2A adenosine receptors modulate coronary vasodilation, A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148–153), and A3 adenosine receptors modulate cell proliferation processes.
A1 adenosine receptor agonists modulates the cardiostimulatory effects of catecholamine (mediated via the inhibition of adenylate cyclase), and slows the heart rate (HR) and prolongs impulse propagation through the AV node, which is due in great part to activation of IKAdo. (B. Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P 1499–1509 and J. C. Shryock and L. Belardinelli The Am. J. Cardiology, Vol. 79 (1997) P 2–10). Stimulation of the A1 adenosine receptor shortens the duration and decreases the amplitude of the action potential of AV nodal cells, and hence prolongs the refractory period of the AV nodal cell. Thus, stimulation of A1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter.
A1 agonists are also useful for emesis, and for treating non-insulin-dependent diabetes mellitus, hyperglycemia, epilepsy (anticonvulsant activity), and provide cardio-and neuro-protection. They also have antilipolytic effects in adipocytes leading to decreased release of free fatty acids.
Accordingly, it is an object of this invention to provide compounds that are potent full A1 adenosine receptor agonists or partial A1 receptor agonists with a half life greater than that of adenosine. Preferred compounds of the invention are selective for the A1 adenosine receptor, which minimizes undesired side effects related to stimulation or antagonism of the other adenosine receptors.